Anti-angiogenesis triggers exosomes release from endothelial cells to promote tumor vasculogenesis

Area of Science:

• Oncology
• Cell Biology
• Biochemistry

Background:

• Anti-angiogenic therapies (AATs) show promise against cancers but are often limited by tumor regrowth.
• Tumor progression following AATs involves complex mechanisms including vasculogenesis and endothelial cell changes.

Purpose of the Study:

• To investigate the mechanisms driving tumor vasculogenesis and progression after AATs.
• To explore the role of microRNA-9 (miR-9) and vascular endothelial growth factor (VEGF)-enriched exosomes in hepatocellular carcinoma (HCC) progression.

Main Methods:

• Transfection of miR-9 into human umbilical vein endothelial cells (HUVECs) to model tumor-associated endothelial cells.
• In vitro and in vivo simulation of AATs using vandetanib and anti-autophagic agents (3-methyladenine).
• Analysis of exosome release, angiogenesis, autophagy, and vasculogenic mimicry in HCC models.

Main Results:

• Vandetanib treatment abolished miR-9-induced angiogenesis but increased autophagy and VEGF-enriched exosome release in HUVECs.
• VEGF-enriched exosomes significantly promoted endothelial vessel formation and vasculogenic mimicry in HCC, driving tumor progression in mice.
• Anti-autophagic therapy showed similar effects to AATs, suggesting a common underlying mechanism.

Conclusions:

• Tumor vasculogenesis and progression following AATs and anti-autophagic therapies are mediated by endothelial-tumor cell crosstalk.
• VEGF-enriched exosomes play a critical role in this crosstalk, promoting HCC progression.
• Targeting exosome-mediated communication could be a strategy to enhance AAT efficacy.